Rhogef12 is a therapeutic target for the treatment of heart failure

Abstract

The present invention relates to an inhibitor of the Rho guanine nucleotide exchange factor 12 (RhoGEF12) or an inhibitor of an activator of RhoGEF12 for use in the prevention and/or treatment of heart failure associated with cardiac hypertrophy and/or cardiac fibrosis and diseases associated therewith. Further, it relates also a method of treatment and methods for identifying inhibitors of Rho guanine nucleotide exchange factor 12 (RhoGEF12) or inhibitors of an activator of RhoGEF12.

1 . (canceled) 
     
     
         2 . A method of preventing and/or treating heart failure associated with cardiac hypertrophy and/or cardiac fibrosis and diseases associated therewith comprising administering a pharmaceutically effective amount of an inhibitor of Rho guanine nucleotide exchange factor 12 (RhoGEF12) or an inhibitor of an activator of RhoGEF12 to a subject in need thereof. 
     
     
         3 . The method of  claim 2 , wherein the inhibitor is an antibody or a fragment or derivative thereof, an aptamer, an siRNA, an shRNA, a miRNA, a ribozyme, an antisense nucleic acid molecule, a small molecule or modified versions of these inhibitors. 
     
     
         4 . The method of  claim 2  or  3 , wherein the activator of RhoGEF12 is the G-protein alpha subunit Gα 13 . 
     
     
         5 . A method of identifying an inhibitor of Rho guanine nucleotide exchange factor 12 (RhoGEF12) or an inhibitor of an activator of RhoGEF12 suitable as a lead compound and/or as a medicament for the prevention and/or treatment of heart failure associated with cardiac hypertrophy and/or cardiac fibrosis and diseases associated therewith, comprising the steps of:
 (a) determining the level of RhoGEF12 protein, the level of RhoGEF12 transcript and/or the level of activity of RhoGEF12 in a cell;   (b) contacting said cell or a cell of the same cell population with a test compound;   (c) determining the level of RhoGEF12 protein, the level of RhoGEF12 transcript and/or the level of activity of RhoGEF12 in said cell after contacting with the test compound; and   (d) comparing the level of RhoGEF12 protein, the level of RhoGEF12 transcript and/or the level of activity of RhoGEF12 determined in step (c) with the RhoGEF12 protein, the RhoGEF12 transcript and/or the RhoGEF12 activity level determined in step (a), wherein a decrease of the RhoGEF12 protein, the RhoGEF12 transcript and/or the RhoGEF12 activity level in step (c) as compared to step (a) indicates that the test compound is an inhibitor of RhoGEF12 or an inhibitor of an activator of RhoGEF12 suitable as a lead compound and/or as a medicament for the prevention and/or treatment of heart failure associated with cardiac hypertrophy and/or cardiac fibrosis and diseases associated therewith.   
     
     
         6 . A method of identifying an inhibitor of Rho guanine nucleotide exchange factor 12 (RhoGEF12) or an inhibitor of an activator of RhoGEF12 suitable as a lead compound and/or as a medicament for the prevention and/or treatment of heart failure associated with cardiac hypertrophy and/or cardiac fibrosis and diseases associated therewith, comprising the steps of:
 (a) determining the level of activity of an RhoGEF12 target molecule in a cell containing RhoGEF12;   (b) contacting said cell or a cell of the same cell population with a test compound;   (c) determining the level of activity of the RhoGEF12 target molecule in said cell after contacting with the test compound; and   (d) comparing the level of activity of the RhoGEF12 target molecule determined in step (c) with the level of activity of the RhoGEF12 target molecule determined in step (a), wherein a decreased activity of the target molecule in step (c) as compared to step (a) indicates that the test compound is an inhibitor of RhoGEF12 or an inhibitor of an activator of RhoGEF12 suitable as a lead compound and/or as a medicament for the prevention and/or treatment of heart failure associated with cardiac hypertrophy and/or cardiac fibrosis and diseases associated therewith.   
     
     
         7 . The method of  claim 6 , wherein the RhoGEF12 target molecule is selected from the GTPase RhoA and the serum response factor (SRF). 
     
     
         8 . The method of any one of  claims 5  to  7 , wherein said cell comprising the RhoGEF12 protein and/or transcript is a cardiomyocyte. 
     
     
         9 . The method of any one of  claims 5  to  8 , further comprising optimising the pharmacological properties of an inhibitor of Rho guanine nucleotide exchange factor 12 (RhoGEF12) or an inhibitor of an activator of RhoGEF12 identified as lead compound. 
     
     
         10 . The method of  claim 9 , wherein the optimisation comprises modifying the inhibitor of RhoGEF12 or the inhibitor of an activator of RhoGEF12 to achieve:
 i) modified spectrum of activity, organ specificity, and/or   ii) improved potency, and/or   iii) decreased toxicity (improved therapeutic index), and/or   iv) decreased side effects, and/or   v) modified onset of therapeutic action, duration of effect, and/or   vi) modified pharmacokinetic parameters (resorption, distribution, metabolism and excretion), and/or   vii) modified physico-chemical parameters (solubility, hygroscopicity, color, taste, odor, stability, state), and/or   viii) improved general specificity, organ/tissue specificity, and/or   ix) optimised application form and route   by   (a) esterification of carboxyl groups, or   (b) esterification of hydroxyl groups with carboxylic acids, or   (c) esterification of hydroxyl groups to, e.g. phosphates, pyrophosphates or sulfates or hemi-succinates, or   (d) formation of pharmaceutically acceptable salts, or   (e) formation of pharmaceutically acceptable complexes, or   (f) synthesis of pharmacologically active polymers, or   (g) introduction of hydrophilic moieties, or   (h) introduction/exchange of substituents on aromates or side chains, change of substituent pattern, or   (i) modification by introduction of isosteric or bioisosteric moieties, or   (j) synthesis of homologous compounds, or   (k) introduction of branched side chains, or   (l) conversion of alkyl substituents to cyclic analogues, or   (m) derivatisation of hydroxyl groups to ketales, acetales, or   (n) N-acetylation to amides, phenylcarbamates, or   (o) synthesis of Mannich bases, imines, or   (p) transformation of ketones or aldehydes to Schiff's bases, oximes, acetales, ketales, enolesters, oxazolidines, thiazolidines   or combinations thereof.   
     
     
         11 . The method of any one of  claims 2  to  10 , wherein the heart failure is associated with cardiac hypertrophy and/or cardiac fibrosis results from diseases and conditions selected from the group consisting of arterial hypertension, valve disease, aortic coarctation, cardiomyophaty and myocardial infarction. 
     
     
         12 . The method of any one of  claims 2  to  11 , wherein the diseases associated with said heart failure are selected from the group consisting of dyspnea, exercise intolerance, pulmonary edema, peripheral edema, nocturia, ascites and hepatomegaly. 
     
     
         13 . A method of preventing or reducing hypertrophy and/or fibrosis of cardiomyocytes comprising: contacting said cardiomyocytes with an effective amount of an inhibitor of the Rho guanine nucleotide exchange factor 12 (RhoGEF12) or an inhibitor of an activator of RhoGEF12. 
     
     
         14 . (canceled)